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Another study showing that higher physical activity (from a variety of activities) is "related to larger gray matter volume in the elderly, regardless of cognitive status", specifically in gray matter areas of the brain responsible for memory, learning, and cognition. In other words, higher levels of physical activity reduce brain atrophy that occurs with aging and improves cognitive function in elderly individuals.  There is also discussion of higher activity levels improving cerebral (brain) blood flow. Bottom line: get off your butt and move more for better brain health. From Medical Xpress:

Burning more calories linked with greater gray matter volume, reduced Alzheimer's risk

Whether they jog, swim, garden or dance, physically active older persons have larger gray matter volume in key brain areas responsible for memory and cognition, according to a new study by researchers at the University of Pittsburgh School of Medicine and UCLA.The findings, published today in the Journal of Alzheimer's Disease, showed also that people who had Alzheimer's disease or mild cognitive impairment experienced less gray matter volume reduction over time if their exercise-associated calorie burn was high.

A growing number of studies indicate physical activity can help protect the brain from cognitive decline, said investigator James T. Becker, Ph.D., professor of psychiatry, Pitt School of Medicine..... "Our study is one of the largest to examine the relationship between physical activity and cognitive decline, and the results strongly support the notion that staying active maintains brain health."

Led by Cyrus Raji, M.D., Ph.D., formerly a student at Pitt School of Medicine and now a senior radiology resident at UCLA, the team examined data obtained over five years from nearly 876 people 65 or older participating in the multicenter Cardiovascular Health Study. All participants had brain scans and periodic cognitive assessments. They also were surveyed about how frequently they engaged in physical activities, such as walking, tennis, dancing and golfing, to assess their calorie expenditure or energy output per week.

Using mathematical modeling, the researchers found that the individuals who burned the most calories had larger gray matter volumes in the frontal, temporal and parietal lobes of the brain, areas that are associated with memory, learning and performing complex cognitive tasks. In a subset of more than 300 participants at the Pitt site, those with the highest energy expenditure had larger gray matter volumes in key areas on initial brain scans and were half as likely to have developed Alzheimer's disease five years later.

"Gray matter houses all of the neurons in your brain, so its volume can reflect neuronal health," Dr. Raji explained. "We also noted that these volumes increased if people became more active over five years leading up to their brain MRI."

 Two articles about the link between Alzheimer's disease (AD) and microbes this past week: a study linking periodontal disease and Alzheimer's, and the other a journal editorial (written by an international team of 31 researchers) suggesting that we need to more closely look at the role of microbes in Alzheimer's disease, especially herpes virus, chlamydia and spirochaete bacteria.

This team is suggesting an "infectious cause" for Alzheimer's, an example being the reactivation of herpes simplex virus type 1 (HSV1) in the person. The researchers state that "regarding HSV1, about 100 publications by many groups indicate directly or indirectly that this virus is a major factor in the disease".  The team also mentions the possibility of fungi infection in some cases (see my November 6, 2015 post about a study finding fungal involvement). Both articles mention that treatment of the diseases with some form of antimicrobials or antivirals could possibly treat Alzheimer's disease, and that trails now need to be done.

From Science Daily: Link between gum disease and cognitive decline in Alzheimer’s

A new study has found a link between gum disease and greater rates of cognitive decline in people with early stages of Alzheimer's Disease. Periodontitis or gum disease is common in older people and may become more common in Alzheimer's disease because of a reduced ability to take care of oral hygiene as the disease progresses. Higher levels of antibodies to periodontal bacteria are associated with an increase in levels of inflammatory molecules elsewhere in the body, which in turn has been linked to greater rates of cognitive decline in Alzheimer's disease in previous studies.

The presence of gum disease at baseline was associated with a six-fold increase in the rate of cognitive decline in participants over the six-month follow-up period of the study. Periodontitis at baseline was also associated with a relative increase in the pro-inflammatory state over the six-month follow-up period. The authors conclude that gum disease is associated with an increase in cognitive decline in Alzheimer's Disease, possibly via mechanisms linked to the body's inflammatory response.....However, growing evidence from a number of studies links the body's inflammatory response to increased rates of cognitive decline, suggesting that it would be worth exploring whether the treatment of gum disease might also benefit the treatment of dementia and Alzheimer's Disease.

From Journal of Alzheimer's Disease: Microbes and Alzheimer’s Disease

We are researchers and clinicians working on Alzheimer’s disease (AD) or related topics, and we write to express our concern that one particular aspect of the disease has been neglected, even though treatment based on it might slow or arrest AD progression. We refer to the many studies, mainly on humans, implicating specific microbes in the elderly brain, notably herpes simplex virus type 1 (HSV1), Chlamydia pneumoniae, and several types of spirochaete, in the etiology of AD [1–4]. Fungal infection of AD brain [5, 6] has also been described, as well as abnormal microbiota in AD patient blood [7]. The first observations of HSV1 in AD brain were reported almost three decades ago [8]. The ever-increasing number of these studies (now about 100 on HSV1 alone) warrants re-evaluation of the infection and AD concept.

AD is associated with neuronal loss and progressive synaptic dysfunction, accompanied by the deposition of amyloid-β (Aβ) peptide, a cleavage product of the amyloid-β protein precursor (AβPP), and abnormal forms of tau protein, markers that have been used as diagnostic criteria for the disease [9, 10]. These constitute the hallmarks of AD, but whether they are causes of AD or consequences is unknown. We suggest that these are indicators of an infectious etiology. In the case of AD, it is often not realized that microbes can cause chronic as well as acute diseases; that some microbes can remain latent in the body with the potential for reactivation, the effects of which might occur years after initial infection; and that people can be infected but not necessarily affected, such that ‘controls’, even if infected, are asymptomatic [2].

Regarding HSV1, about 100 publications by many groups indicate directly or indirectly that this virus is a major factor in the disease....The only opposing reports, two not detecting HSV1 DNA in elderly brains and another not finding an HSV1–APOE association, were published over a decade ago [76–78]. However, despite all the supportive evidence, the topic is often dismissed as ‘controversial’. One recalls the widespread opposition initially to data showing that viruses cause some types of cancer, and that a bacterium causes stomach ulcers.

In summary, we propose that infectious agents, including HSV1, Chlamydia pneumonia, and spirochetes, reach the CNS and remain there in latent form. These agents can undergo reactivation in the brain during aging, as the immune system declines, and during different types of stress (which similarly reactivate HSV1 in the periphery). The consequent neuronal damage— caused by direct viral action and by virus-induced inflammation— occurs recurrently, leading to (or acting as a cofactor for) progressive synaptic dysfunction, neuronal loss, and ultimately AD.

AD causes great emotional and physical harm to sufferers and their carers, as well as having enormously damaging economic consequences. Given the failure of the 413 trials of other types of therapy for AD carried out in the period 2002–2012 [79], antiviral/antimicrobial treatment of AD patients, notably those who are APOE ɛ 4 carriers, could rectify the ‘no drug works’ impasse. We propose that further research on the role of infectious agents in AD causation, including prospective trials of antimicrobial therapy, is now justified.

Brain aging can be viewed as having 2 parts: chronological age (normally  the brain grey matter volume slowly shrinks with advancing age) and a lifetime of exposures - which can be negative from unhealthy lifestyle and injuries, and positive from a healthy lifestyle and enriched environments. That's why after a lifetime there can be wide variation in the physiological age of our brains. These differences in the  brain (in the grey matter) can be measured with magnetic resonance imaging (MRIs).

The researchers in this study used the concept of physiological age - the difference between the chronological age and predicted age, as a marker of brain health. They looked at adults of varying ages,and found that the more flights of stairs a person climbs daily, and the more years of school a person had completed, the "younger" their brain physically appears.  This study was a cross-sectional study and so shows an association rather than a definite cause, but interestingly other forms of exercise did not show this link (walking/hiking, jogging, running, bicycling, aerobic exercise, lap swimming, tennis.squash/racquetball, low intensity exercise). From Science Daily:

Want a younger brain? Stay in school -- and take the stairs

Taking the stairs is normally associated with keeping your body strong and healthy. But new research shows that it improves your brain's health too -- and that education also has a positive effect. In a study recently published in the journal Neurobiology of Aging, researchers led by Jason Steffener, a scientist at Concordia University's Montreal-based PERFORM Centre, show that the more flights of stairs a person climbs, and the more years of school a person completes, the "younger" their brain physically appears.

The researchers found that brain age decreases by 0.95 years for each year of education, and by 0.58 years for every daily flight of stairs climbed -- i.e., the stairs between two consecutive floors in a building.

For the study, Steffener and his co-authors used magnetic resonance imaging (MRI) to non-invasively examine the brains of 331 healthy adults who ranged in age from 19 to 79. They measured the volume of grey matter found in participants' brains because its decline, caused by neural shrinkage and neuronal loss, is a very visible part of the chronological aging process. Then, they compared brain volume to the participants' reported number of flights of stairs climbed, and years of schooling completed. 

Results were clear: the more flights of stairs climbed, and the more years of schooling completed, the younger the brain. "This study shows that education and physical activity affect the difference between a physiological prediction of age and chronological age, and that people can actively do something to help their brains stay young," he says.

A new study has confirmed an association between proton pump inhibitors (PPIs) — drugs that treat heartburn, peptic ulcers, and other acid-related disorders of the upper gastrointestinal tract — and increased risk for dementia in older patients. An earlier study by the same researchers found the same link between PPI use and dementia risk. The drugs work by lowering the amount of acid produced by the stomach. PPIs are among the most frequently prescribed drugs, and include omeprazole (Losec), esomeprazole (Nexium), lansoprazole (Prevacid), and the over-the-counter medication Olex.

The U.S. Food and Drug Administration have warned people to take them for the shortest period possible, namely a few weeks, and only for serious acid reflux, ulcers, or stomach bleeding. Other problems linked to long-term use are: fractures, pneumonia, increased rates of C. difficile, low magnesium levels, and chronic kidney disease. From Science Daily:

Proton pump inhibitors may be associated with increased risk of Dementia

The use of proton pump inhibitors, the popular medications used to treat gastroesophageal reflux and peptic ulcers, may be associated with an increased risk of dementia in a study using data from a large German health insurer, according to an article published online by JAMA Neurology.  The use of proton pump inhibitors (PPIs) has increased among older patients and PPIs are among the most frequently used classes of drugs.

Britta Haenisch, Ph.D., of the German Center for Neurodegenerative Diseases, Bonn, Germany, and coauthors examined the association between the use of PPIs and the risk of dementia using data from 2004 to 2011 on inpatient and outpatient diagnoses and drug prescriptions. Regular PPI use was at least one PPI prescription in each quarter of an 18-month interval.

The study population included 218,493 individuals 75 or older before 144,814 individuals were excluded, leaving 73,679 individuals included in the final analysis. The authors identified 29,510 patients who developed dementia during the study period. Regular users of PPIs (2,950 patients, mostly female and average age nearly 84) had a 44 percent increased risk of dementia compared with those (70,729 patients, mostly female and average age 83) not receiving PPI medication, according to the results.

"The present study can only provide a statistical association between PPI use and risk of dementia. The possible underlying causal biological mechanism has to be explored in future studies. 

The finding that the oral bacteria Streptococcus mutans, which is found in 10% of the population, is linked with hemorrhagic strokes is big. S. mutans is found in tooth decay or cavities (dental caries). The researchers found a link with cnm-positive S. mutans with both intracerebral hemorrhage (ICH) and also with cerebral microbleeds.

Some risk factors for strokes have long since been known, such as high blood pressure and advanced age, but then there are those hemorrhagic strikes that don't seem to fit the norm, with no apparent risk factors. Well, apparently the presence of cnm-positive S. mutans is one. My understanding of what cnm-positive S. mutans means is S. mutans bacteria that carries the collagen-binding Cnm gene. This bacteria can be found in a person's saliva and in dental plaque, and swabs of both were taken for this study.

This study builds on other studies that find a link between the bacteria Streptococcus mutans and a number of systemic diseases, including bacteremia, infective endocarditis and hemorrhagic stroke. The researchers of this latest study suggest that infection with cnm-positive S. mutans causes constant inflammation (as shown by 2 inflammatory markers: CRP and fibrinogen), which then causes damage to blood vessels (endothelial damage) in the brain. Bottom line: take care of your teeth and gums.

From Science Daily: Oral bacteria linked to risk of stroke

In a study of patients entering the hospital for acute stroke, researchers have increased their understanding of an association between certain types of stroke and the presence of the oral bacteria (cnm-positive Streptococcus mutans).

In the single hospital study, researchers at the National Cerebral and Cardiovascular Center in Osaka, Japan, observed stroke patients to gain a better understanding of the relationship between hemorrhagic stroke and oral bacteria. Among the patients who experienced intracerebral hemorrhage (ICH), 26 percent were found to have a specific bacterium in their saliva, cnm-positive S. mutans. Among patients with other types of stroke, only 6 percent tested positive for the bacterium.

Strokes are characterized as either ischemic strokes, which involve a blockage of one or more blood vessels supplying the brain, or hemorrhagic strokes, in which blood vessels in the brain rupture, causing bleeding.

The researchers also evaluated MRIs of study subjects for the presence of cerebral microbleeds (CMB), small brain hemorrhages which may cause dementia and also often underlie ICH. They found that the number of CMBs was significantly higher in subjects with cnm-positive S. mutans than in those without. The authors hypothesize that the S. mutans bacteria may bind to blood vessels weakened by age and high blood pressure, causing arterial ruptures in the brain, leading to small or large hemorrhages.

"This study shows that oral health is important for brain health. People need to take care of their teeth because it is good for their brain and their heart as well as their teeth," Friedland said. "The study and related work in our labs have shown that oral bacteria are involved in several kinds of stroke, including brain hemorrhages and strokes that lead to dementia."

Multiple research studies have shown a close association between the presence of gum disease and heart disease, and a 2013 publication by Jan Potempa, Ph.D., D.Sc., of the UofL School of Dentistry, revealed how the bacterium responsible for gum disease worsens rheumatoid arthritisThe cnm-negative S. mutans bacteria is found in approximately 10 percent of the general population, Friedland says, and is known to cause dental cavities (tooth decay). Friedland also is researching the role of oral bacteria in other diseases affecting the brain.  http://www.nature.com/articles/srep20074

Another famous long-running study (Framingham Heart Study) finds more bad news for middle-aged coach-potatoes (that is, those who don't exercise or have poor physical fitness). It's an observational study (thus they found an association), but the finding is pretty damn convincing: that poor physical fitness (basically a sedentary life-style) may be linked to a smaller brain size (brain volume) 20 years later. The reason this is significant is because shrinking brain volume means that accelerated brain aging is occurring.

Researcher Nicole Spartano said: "Brain volume is one marker of brain aging. Our brains shrink as we age, and this atrophy is related to cognitive decline and increased risk for dementia. So, this study suggests that people with poor fitness have accelerated brain aging." Bottom line: if you don't get much exercise or lead a sedentary life-style, then increase your activity levels for hopefully better brain health decades later. Just getting out daily (or several times a week) and walking briskly would improve fitness. From Medical Xpress:

Couch potatoes may have smaller brains later in life

Poor physical fitness in middle age may be linked to a smaller brain size 20 years later, according to a study published in the February 10, 2016, online issue of Neurology, the medical journal of the American Academy of Neurology."We found a direct correlation in our study between poor fitness and brain volume decades later, which indicates accelerated brain aging," said study author Nicole Spartano, PhD, with Boston University School of Medicine in Boston.

For the study, 1,583 people enrolled in the Framingham Heart Study, with an average age of 40 and without dementia or heart disease, took a treadmill test. They took another one two decades later, along with MRI brain scans. The researchers also analyzed the results when they excluded participants who developed heart disease or started taking beta blockers to control blood pressure or heart problems; this group had 1,094 people. 

The participants had an average estimated exercise capacity of 39 mL/kg/min, which is also known as peak VO2, or the maximum amount of oxygen the body is capable of using in one minute. Exercise capacity was estimated using the length of time participants were able to exercise on the treadmill before their heart rate reached a certain level. For every eight units lower a person performed on the treadmill test, their brain volume two decades later was smaller, equivalent to two years of accelerated brain aging. When the people with heart disease or those taking beta blockers were excluded, every eight units of lower physical performance was associated with reductions of brain volume equal to one year of accelerated brain aging.

The study also showed that people whose blood pressure and heart rate went up at a higher rate during exercise also were more likely to have smaller brain volumes two decades later. Spartano said that people with poor physical fitness often have higher blood pressure and heart rate responses to low levels of exercise compared to people with better fitness. Spartano noted that the study is observational. It does not prove that poor physical fitness causes a loss of brain volume; it shows the association. (Link to study in journal Neurology.)

More evidence that traditional toys and books are superior to electronic toys in both verbal parent-child interactions and non-verbal interactions for young children. Parent-child verbal interactions are so important because they teach young children language, lay the groundwork for literacy skills, teach role-playing, teach emotional and social skills such as turn-taking and accepting others' leads. In other words, put down the electronic gadgets and go spend time talking and interacting with your young child with old style traditional toys and books. From Science Daily:

How does type of toy affect quantity, quality of language in infant playtime?

Electronic toys for infants that produce lights, words and songs were associated with decreased quantity and quality of language compared to playing with books or traditional toys such as a wooden puzzle, a shape-sorter and a set of rubber blocks, according to an article published online by JAMA Pediatrics.

Anna V. Sosa, Ph.D., of Northern Arizona University, Flagstaff, and colleagues conducted a controlled experiment involving 26 parent-infant pairs with children who were 10 to 16 months old. Researchers did not directly observe parent-infant play time because it was conducted in participants' homes. Audio recording equipment was used to pick up sound. Participants were given three sets of toys: electronic toys (a baby laptop, a talking farm and a baby cell phone); traditional toys (chunky wooden puzzle, shape-sorter and rubber blocks with pictures); and five board books with farm animal, shape or color themes.

While playing with electronic toys there were fewer adult words used, fewer conversational turns with verbal back-and-forth, fewer parental responses and less production of content-specific words than when playing with traditional toys or books. Children also vocalized less while playing with electronic toys than with books, according to the results.

Results also indicate that parents produced fewer words during play with traditional toys than while playing with books with infants. Parents also used less content-specific words when playing with traditional toys with their infants than when playing with books. The authors note results showed the largest and most consistent differences between electronic toys and books, followed by electronic toys and traditional toys.

"These results provide a basis for discouraging the purchase of electronic toys that are promoted as educational and are often quite expensive. These results add to the large body of evidence supporting the potential benefits of book reading with very young children. They also expand on this by demonstrating that play with traditional toys may result in communicative interactions that are as rich as those that occur during book reading. ... However, if the emphasis is on activities that promote a rich communicative interaction between parents and infants, both play with traditional toys and book reading can be promoted as language-facilitating activities while play with electronic toys should be discouraged," the study concludes.

EDITORIAL: "Electronic toys that make noises or light up are extremely effective at commanding children's attention by activating their orienting reflex. This primitive reflex compels the mind to focus on novel visual or auditory stimuli. The study by Sosa in this issue of JAMA Pediatrics suggests that they may do more than just command children's attention; they appear to reduce parent-child verbal interactions. Why does this matter? Conversational turns during play do more than teach children language. They lay the groundwork for literacy skills, teach role-playing, give parents a window into their child's developmental stage and struggles, and teach social skills such as turn-taking and accepting others' leads.

Verbal interactions of course are only part of the story. What is missing from this study is a sense of how nonverbal interactions, which are also an important source of social and emotional skills, varied by toy type," write Jenny S. Radesky, M.D., of the University of Michigan Medical School, Ann Arbor, and Dimitri A. Christakis, M.D., M.P.H., of Seattle Children's Hospital and a JAMA Pediatrics associate editor, in a related editorial.

A large study found that using antidepressants during the second or third trimester of pregnancy increases the risk that the child will have autism by 87%,  especially if the mother takes selective serotonin reuptake inhibitors (SSRIs). A drawback was that the study looked at associations rather than actual cause (which would have meant randomly assigning women to either treatment or no treatment - which is unethical). From Medical Xpress:

Taking antidepressants during pregnancy increases risk of autism by 87 percent

Using antidepressants during pregnancy greatly increases the risk of autism, Professor Anick Bérard of the University of Montreal and its affiliated CHU Sainte-Justine children's hospital revealed today. Prof. Bérard, an internationally renowned expert in the fields of pharmaceutical safety during pregnancy, came to her conclusions after reviewing data covering 145,456 pregnancies.

"The variety of causes of autism remain unclear, but studies have shown that both genetics and environment can play a role," she explained. "Our study has established that taking antidepressants during the second or third trimester of pregnancy almost doubles the risk that the child will be diagnosed with autism by age 7, especially if the mother takes selective serotonin reuptake inhibitors, often known by its acronym SSRIs." Her findings were published today in JAMA Pediatrics.

Bérard and her colleagues worked with data from the Quebec Pregnancy Cohort and studied 145,456 children between the time of their conception up to age ten. In addition to information about the mother's use of antidepressants and the child's eventual diagnosis of autism, the data included a wealth of details that enabled the team to tease out the specific impact of the antidepressant drugs. 

"We defined exposure to antidepressants as the mother having had one or more prescription for antidepressants filled during the second or third trimester of the pregnancy. This period was chosen as the infant's critical brain development occurs during this time," Prof. Bérard said. "Amongst all the children in the study, we then identified which children had been diagnosed with a form of autism by looking at hospital records indicating diagnosed childhood autism, atypical autism, Asperger's syndrome, or a pervasive developmental disorder. Finally, we looked for a statistical association between the two groups, and found a very significant one: an 87% increased risk." 

The findings are hugely important as six to ten percent of pregnant women are currently being treated for depression with antidepressants. In the current study, 1,054 children were diagnosed with autism (0.72% of the children in the study), on average at 4.5 years of age. Moreover, the prevalence of autism amongst children has increased from 4 in 10,000 children in 1966 to 100 in 10,000 today. While that increase can be attributed to both better detection and widening criteria for diagnosis, researchers believe that environmental factors are also playing a part.

"It is biologically plausible that anti-depressants are causing autism if used at the time of brain development in the womb, as serotonin is involved in numerous pre- and postnatal developmental processes, including cell division, the migration of neuros, cell differentiation and synaptogenesis - the creation of links between brain cells," Prof. Bérard explained. "Some classes of anti-depressants work by inhibiting serotonin (SSRIs and some other antidepressant classes), which will have a negative impact on the ability of the brain to fully develop and adapt in-utero".

New research showed that eight days after a concussion, the concussed athletes (football players) looked and felt like they had recovered (clinical recovery), but MRIs showed that there were still neurophysiological abnormalities (significant blood flow decrease) in their brains. They did not look at if and when the blood flow returned to normal, but that research also needs to be done.

It is very disturbing to look at both this research and also the finding that the off-season is not enough for high school football players to recover from the repeated hits (not concussions, but sub-concussive hits) that they receive during the football season (Nov. 24, 2015 post). Do student football players really know and understand the dangers to their brains from the repeated hits and also concussions that occur in football? From Medical Xpress:

Reduced blood flow seen in brain after clinical recovery of acute concussion

Some athletes who experience sports-related concussions have reduced blood flow in parts of their brains even after clinical recovery, according to a study presented today at the annual meeting of the Radiological Society of North America (RSNA). The results suggest a role for MRI in determining when to allow concussed athletes to return to competition.

Decisions to clear concussed athletes to return to action are typically based on symptoms and cognitive and neurological test results. However, there is increasing evidence that brain abnormalities persist beyond the point of clinical recovery after injury. To find out more, researchers from the Medical College of Wisconsin in Milwaukee studied concussed football players with arterial spin labeling, an advanced MRI method that detects blood flow in the brain.

Dr. Wang and colleagues studied 18 concussed players and 19 non-concussed players. They obtained MRI of the concussed players within 24 hours of the injury and a follow-up MRI eight days after the injury and compared results with those of the non-concussed players. Clinical assessments were obtained for both groups at each time point, as well as at the baseline before the football season.

The concussed players demonstrated significant impairment on clinical assessment at 24 hours post-injury, but returned to baseline levels at eight days. In contrast to clinical manifestation, the concussed players demonstrated a significant blood flow decrease at eight days relative to 24 hours post-injury, while the non-concussed players had no change in cerebral blood flow between the two time points.

"In eight days, the concussed athletes showed clinical recovery," Dr. Wang said. "However, MRI showed that even those in clinical recovery still had neurophysiological abnormalities. Neurons under such a state of physiologic stress function abnormally and may become more susceptible to second injury." "For years, we've relied on what athletes are telling us," Dr. McCrea said. "We need something more objective, and this technology may provide a greater measurement of recovery."

This past week there was discussion of the number of high school football players that die annually while playing football (at least 5). But the bigger risk - because it involves so many players - is the damage to brains that occurs from concussions and from just being hit in football. The response from football enthusiasts is that there are safeguards now - that football players don't play after a concussion until they "heal" (show no obvious symptoms). But do they really heal? And much of the damage is from repeated hits, without having a concussion (sub-concussive blows or hits), what about the damage from that?

This study found that repeated head hits in football can cause changes in brain chemistry and metabolism, even in high school players not diagnosed with concussions. And even after the lengthy off-season (somewhere between two and five months after the season has ended)—the majority of players are still showing that they had not fully recovered. The researchers also made it clear that 2 weeks is not enough time to heal from a concussion. Scary long-term implications - what is happening to brains that never truly heal from past seasons as the players start playing in the next season? From Futurity:

High School Football: Teen Brains Don't Heal During Offseason

Brain scans of high school football players taken before, during, and after the season raise concerns they don’t fully recover from repeated head hits. The researchers used an imaging technique called proton magnetic resonance spectroscopy (1H MRS) to study the brains of 25 high school football players and compared them to the brains of teenagers involved in non-contact sports. The findings suggest repeated head hits in football can cause changes in brain chemistry and metabolism, even in players not diagnosed with concussions. 

We are seeing damage not just to neurons, but also to the vasculature and glial cells in the brain,” says Eric Nauman, professor of mechanical engineering, basic medical sciences, and biomedical engineering at Purdue University. “I was particularly disturbed that when you get to the offseason—we are looking somewhere between two and five months after the season has ended—the majority of players are still showing that they had not fully recovered.”

The 1H MRS data provide details about the blood flow, metabolism, and chemistry of neurons and glial cells important for brain function. The data also revealed a “hypermetabolic response” during the preseason, as though the brain was trying to heal connections impaired from the previous season. “We found that in the preseason for the football players in our study, one part of the brain would be associating with about 100 other regions, which is much higher than the controls,” says Thomas Talavage,  professor of electrical and computer engineering and biomedical engineering and co-director of the Purdue MRI Facility.

“The brain is pretty amazing at covering up a lot of changes. Some of these kids have no outward symptoms, but we can see their brains have rewired themselves to skip around the parts that are affected.”

One of the research papers shows that knowing a player’s history of specific types of hits to the head makes it possible to accurately predict “deviant brain metabolism,” suggesting that sub-concussive blows can produce biochemical changes and potentially lead to neurological problems, which indicates a correlation between players taking the heaviest hits and brain chemistry changes.

The data shows that the neurons in the motor cortex region in the brains of football players produced about 50 percent less of the neurotransmitter glutamine compared to controls. “We are finding that the more hits you take, the more you change your brain chemistry, the more you change your brain’s ability to move blood to the right locations,” Nauman says.

“Recent proton magnetic resonance spectroscopy studies argue that the recommended two-week window of rest is insufficient for full metabolic recovery after concussion,” Nauman says. “Those returning to play prior to full recovery could incur a second concussion with symptoms and metabolic changes more lasting than the first.”